U.S. patent application number 15/714518 was filed with the patent office on 2018-01-18 for thermally conductive graft.
The applicant listed for this patent is University of Washington, Washington University in St. Louis. Invention is credited to Samuel R. Browd, Raimondo D'Ambrosio, Clifford L. Eastman, Jason Fender, John W. Miller, Jeffrey G. Ojemann, Steven M. Rothman, Matthew Smyth.
Application Number | 20180014971 15/714518 |
Document ID | / |
Family ID | 56978638 |
Filed Date | 2018-01-18 |
United States Patent
Application |
20180014971 |
Kind Code |
A1 |
D'Ambrosio; Raimondo ; et
al. |
January 18, 2018 |
THERMALLY CONDUCTIVE GRAFT
Abstract
The present disclosure provides thermally conductive grafts and
methods of passively cooling a hyperthermic region and preventing
epilepsy, neural inflammation, and other neurological abnormalities
using a thermally conductive graft including a thermally conductive
matrix disposed between two opposed surfaces.
Inventors: |
D'Ambrosio; Raimondo;
(Seattle, WA) ; Browd; Samuel R.; (Seattle,
WA) ; Miller; John W.; (Bellevue, WA) ;
Ojemann; Jeffrey G.; (Seattle, WA) ; Eastman;
Clifford L.; (Seattle, WA) ; Smyth; Matthew;
(Frontenac, MO) ; Rothman; Steven M.; (Clayton,
MO) ; Fender; Jason; (Bonney Lake, WA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
University of Washington
Washington University in St. Louis |
Seattle
St. Louis |
WA
MO |
US
US |
|
|
Family ID: |
56978638 |
Appl. No.: |
15/714518 |
Filed: |
September 25, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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PCT/US2016/024281 |
Mar 25, 2016 |
|
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15714518 |
|
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62138173 |
Mar 25, 2015 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61F 7/12 20130101; A61F
2007/0002 20130101 |
International
Class: |
A61F 7/12 20060101
A61F007/12 |
Claims
1. A thermally conductive graft comprising: a first surface; a
second surface; and a thermally conductive matrix disposed between
the first and second surfaces.
2. The thermally conductive graft of claim 1, wherein the thermally
conductive matrix comprises: a biocompatible matrix and a thermally
conductive material embedded into the biocompatible matrix.
3. The thermally conductive graft of claim 2, wherein the thermally
conductive material comprises one or more of the following:
thermally conductive polymers, graphene, carbon nanotubes, diamond,
metal powders, metal beads, and combinations thereof.
4. The thermally conductive graft of claim 2, wherein the
biocompatible matrix comprises one or more of the following:
silicon, collagen, expanded polytetrafluoroethylene, polylactide,
polyglycolide, gelatin, agar, cellulose, thermally conductive
polymer, carbohydrate chain, collagen autograph, allograph,
xenograph, and combinations thereof.
5. The thermally conductive graft of claim 1, wherein the thermally
conductive graft is sized and configured to: (1) overlay a
meningeal membrane under a skull of a human subject; or (2) replace
a portion of the meningeal membrane of the human subject.
6. The thermally conductive graft of claim 1, wherein the thermally
conductive graft is sized and configured to extend from a dural
space through a channel in a skull to a subgaleal space of a human
subject.
7. The thermally conductive graft of claim 1, wherein the thermally
conductive matrix comprises a biocompatible polymer matrix.
8. The thermally conductive graft of claim 1, wherein the thermally
conductive graft is between 0.1 mm and 8 mm thick.
9. The thermally conductive graft of claim 1, wherein the second
surface comprises a coating which is adhesive to a meninges of a
human subject.
10. The thermally conductive graft of claim 1, wherein the second
surface comprises a coating which is non-scarring to a meninges of
a human subject.
11. The thermally conductive graft of claim 1, further comprising a
non-fouling coating on one or more of the first surface and the
second surface.
12. The thermally conductive graft of claim 1, further comprising
at least one aperture disposed in the thermally conductive matrix
sized and configured to allow fluid to drain from one substantially
planar opposed surface to the other.
13. The thermally conductive graft of claim 1, further comprising
at least one aperture disposed in the thermally conductive matrix
having a first and a second end sized and configured to allow fluid
to drain laterally from portion of the thermally conductive graft
to the other.
14. The thermally conductive graft of claim 1, wherein the first
surface is substantially planar and the second surface is
substantially planar.
15. A method of passively cooling a hyperthermic region of a
central nervous system of a human subject, the method comprising:
implanting a thermally conductive graft adjacent to the
hyperthermic region of the central nervous system, wherein the
thermally conductive graft is effective to conduct heat from the
hyperthermic region to another region.
16. The method of claim 15, further comprising: making an incision
in a scalp of a subject; removing a portion of a cranium through
the incision to form a recess in which a portion of a meningeal
membrane adjacent to the hyperthermic region is exposed; and
implanting the thermally conductive graft adjacent to the exposed
meningeal membrane.
17. The method of claim 15, wherein the thermally conductive graft
comprises: a first surface; a second surface; and a thermally
conductive matrix disposed between the first and second
surfaces.
18. The method of claim 17, wherein the thermally conductive matrix
comprises a biocompatible matrix and a thermally conductive
material embedded in the biocompatible matrix.
19. The method of claim 18, wherein: the thermally conductive
matrix comprises one or more of the following: thermally conductive
polymers, graphene, carbon nanotubes, diamond, metal powders, metal
beads, and combinations thereof; and the biocompatible matrix
comprises one or more of the following: silicon, collagen, expanded
polytetrafluoroethylene, polylactide, polyglycolide, gelatin, agar,
cellulose, thermally conductive polymer, carbohydrate chain,
collagen autograph, allograph, xenograph, and combinations
thereof.
20. The method of claim 15, further comprising: (1) removing a
portion of a dura mater adjacent to the hyperthermic region of the
human subject; or (2) replacing a portion of a cranium of the human
subject adjacent to the hyperthermic region.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of International
Application No. PCT/US2016/024281, filed Mar. 25, 2016, which
claims the benefit of U.S. Provisional Application No. 62/138,173
filed Mar. 25, 2015, entitled "Central Nervous System Graft for the
Treatment of Epilepsy and Neuroinflammation," the contents of each
are incorporated herein by reference in their entirety.
BACKGROUND
[0002] Epilepsy can be understood as a syndrome involving episodic
abnormal electrical activity in the brain, or epileptic seizures,
that result from abnormal, excessive or hypersynchronous neuronal
activity in the brain. It is estimated that 50 million people
worldwide have epilepsy. The onset of epileptic symptoms occurs
most frequently in infants and the elderly, and may also arise from
trauma to the brain or as a consequence of brain surgery.
[0003] Epileptic symptoms are sometimes controllable with
medication. However, nearly one-third (1/3) of persons with
epilepsy cannot control seizures even with the best available
medications. In certain cases, neurosurgery is undertaken to remove
the epileptic focus to control the seizures.
[0004] For example, the high incidences of traumatic brain injury
(TBI) in both the civilian and military populations, and the
absence of any prophylactic treatment for acquired epilepsy, such
as post-traumatic epilepsy (PTE), create an urgent need to develop
broad-spectrum and easily deployable therapeutic strategies. There
are currently no effective means for preventing the onset of PTE
following head injury. The administration of anticonvulsants after
head injury may decrease early post-traumatic seizures but has
failed to impact the development of long-term epilepsy or improve
the incidence of disability or death. Therefore, novel treatment
paradigms are needed.
[0005] The process of epileptogenesis in humans is not known. It is
theorized that agents that are neuro-protective may also be
anti-epileptogenic. Similarly, the process of ictogenesis (i.e.,
the precipitation of seizures) is not necessarily the same as
epileptogenesis. It is, therefore, entirely possible that
treatments that prevent the precipitation of seizures do not
prevent the genesis of epilepsy and, vice versa, those that may
prevent the onset of epilepsy may not be capable of shutting down
existing seizures.
[0006] There are known devices that use active cooling to shut down
epileptic seizures (antiepileptic effect). Many known devices are
based on the assumption that cooling a targeted area of the brain
by about 1.degree. C. is necessary to shut down the epileptic
focus. One such device is based on active Peltier cells that cool
the brain, including heat pipes to cool deep into the brain. A
second known device uses circulating coolant in tubing implanted
within the dorsal hippocampus of a brain to achieve cooling of at
least 7.degree. C. in the hippocampus. Unfortunately, such devices
are typically highly intrusive (if inserted deep into the brain)
and require the implantation of complex structures (e.g., heat
pipes), electronics (e.g., Peltier elements), and long-lasting
powering elements (e.g., batteries) to produce the necessary
cooling.
[0007] Further, epileptic foci generate more heat than surrounding
tissue. Several factors may affect the temperature of defined
regions of brain parenchyma in general, and of an epileptic focus
in particular.
[0008] Neuronal activity results in localized transient temperature
increases. Suzuki et al. (2012) have recently used infrared
thermography to image the activity-induced temperature increases in
the rat barrel cortex in response to whisker stimulation, and shown
the observed changes to be largely independent of changes in
regional cerebral blood flow (rCBF). See Suzuki T, Ooi Y, Seki J.,
Infrared thermal imaging of rat somatosensory cortex with whisker
stimulation. J. Appl. Physiol., 112(7):1215-22 (2012). Thus, the
elevated neuronal activity and supporting metabolism in the
epileptic focus may stably exceed that in adjacent tissue to give
rise to a measurable temperature gradient both inter-ictally and
ictally.
[0009] Inflammation generates heat. Micro-calorimetry studies have
demonstrated that immune cells produce heat upon activation
(Charlebois S J, Daniels A U, Smith R A., Metabolic heat production
as a measure of macrophage response to particles from orthopedic
implant materials, J. Biomed. Mater Res. January; 59(1):166-75
(2002); Hayatsu H, Masuda S, Miyamae T, Yamamura M., Heat
production due to intracellular killing activity, Tokai J. Exp.
Clin. Med. September; 15(5):395-9 (1990); Parsson H, Nassberger L,
Thorne J, Norgren L., Metabolic response of granulocytes and
platelets to synthetic vascular grafts: preliminary results with an
in vitro technique, J. Biomed. Mater Res. April; 29(4):519-25
(1995); Yamamura M, Hayatsu H, Miyamae T, Shimoyama Y., Heat
production as a quantitative parameter for cell differentiation and
cell function, Tokai J. Exp. Clin. Med., September; 15(5):377-80
(1990)). This heat generation may reflect activation-related
increases in the rate of oxidative metabolism, the predominance of
inefficient glycolytic metabolism in some immune cells (Geering B,
Simon H U., Peculiarities of cell death mechanisms in neutrophils,
Cell Death Differ. September; 18(9):1457-69 (1990)), or regulated
uncoupling of mitochondrial respiration, which may play a role in
phagocytosis (Cereghetti G M, Scorrano L. Phagocytosis: coupling of
mitochondrial uncoupling and engulfment., Curr. Biol.;
21(20):R852-4 (2011); Park D, Han C Z, Elliott M R, Kinchen J M,
Trampont P C, Das S, Collins S, Lysiak J J, Hoehn K L, Ravichandran
K S., Continued clearance of apoptotic cells critically depends on
the phagocyte Ucp2 protein, Nature.; 477(7363):220-4 (2011)).
Recent evidence supports an important role for inflammation in
epilepsy (Choi J, Koh S., Role of brain inflammation in
epileptogenesis, Yonsei Med J.; 49(1):1-18 (2008); Fabene P F,
Navarro Mora G, Martinello M, Rossi B, Merigo F, Ottoboni L, Bach
S, Angiari S, Benati D, Chakir A, Zanetti L, Schio F, Osculati A,
Marzola P, Nicolato E, Homeister J W, Xia L, Lowe J B, McEver R P,
Osculati F, Sbarbati A, Butcher E C, Constantin G., A role for
leukocyte-endothelial adhesion mechanisms in epilepsy, Nat. Med.;
14(12):1377-83 (2008); Friedman A, Dingledine R., Molecular
cascades that mediate the influence of inflammation on epilepsy,
Epilepsia., May; 52 Suppl 3:33-9 (2011); Li G, Bauer S, Nowak M,
Norwood B, Tackenberg B, Rosenow F, Knake S, Oertel W H, Hamer H M,
Cytokines and epilepsy, Seizure. April; 20(3):249-56 (2011)), and
leukocyte infiltration has been observed in resected epileptic
brain tissue from temporal lobe epilepsy patients (Zattoni M, Mura
M L, Deprez F, Schwendener R A, Engelhardt B, Frei K, Fritschy J
M., Brain infiltration of leukocytes contributes to the
pathophysiology of temporal lobe epilepsy, J Neurosci.;
31(11):4037-50 (2011), and after status epilepticus, and even
single brief seizures, in rodents (Fabene P F, Navarro Mora G,
Martinello M, Rossi B, Merigo F, Ottoboni L, Bach S, Angiari S,
Benati D, Chakir A, Zanetti L, Schio F, Osculati A, Marzola P,
Nicolato E, Homeister J W, Xia L, Lowe J B, McEver R P, Osculati F,
Sbarbati A, Butcher E C, Constantin G., A role for
leukocyte-endothelial adhesion mechanisms in epilepsy, Nat. Med.;
14(12):1377-83 (2008); Kim et al., 2010; 2012; Silverberg et al.,
2010; Zattoni et al., 2011).
[0010] Regulated mitochondrial uncoupling may contribute
importantly to the elevated temperature of epileptic foci acquired
after brain insult. When mitochondrial respiration is uncoupled
from ATP production, the energy released from glucose oxidation is
dissipated as heat. Three uncoupling proteins (UCP) are expressed
in brain tissue at levels that may differ markedly between species
(Alan L, SmolkovaK, Kronusova E, Santorova J, Jezek P., Absolute
levels of transcripts for mitochondrial uncoupling proteins UCP2,
UCP3, UCP4, and UCP5 show different patterns in rat and mice
tissues, J. Bioenerg. Biomembr.; 41(1):71-8 (2009)). UCP2 mRNA is
ubiquitously expressed in all tissues but is strongly associated
with immune cells (Alan et al., 2009). In the brain, UCP2 protein
is expressed mainly in microglia (Rupprecht A, Brauer A U,
Smorodchenko A, Goyn J, Hilse K E, Shabalina I G, Infante-Duarte C,
Pohl E E., Quantification of uncoupling protein 2 reveals its main
expression in immune cells and selective up-regulation during
T-cell proliferation, PLoS. One.; 7(8):e41406. doi:
10.1371/journal.pone.0041406. (2012)). Other UCP are induced by a
variety of brain injuries, including ischemia-reprofusion, kainic
acid and embolic stroke.
[0011] What is desired, therefore, is an improved device for
preventing and/or treating acquired epilepsy and other neurological
abnormalities.
SUMMARY
[0012] This summary is provided to introduce a selection of
concepts in a simplified form that are further described below in
the Detailed Description. This summary is not intended to identify
key features of the claimed subject matter, nor is it intended to
be used as an aid in determining the scope of the claimed subject
matter.
[0013] Epilepsy can be mitigated or prevented by a method
comprising removing a portion of a cranium through an incision in a
scalp of a patient to form a recess in which a portion of dura
mater is exposed; and implanting a cooling device adjacent the
exposed portion of dura mater and closing the incision such that an
adjacent portion of the brain is cooled by the cooling device by
heat dissipation through the scalp, and wherein the adjacent
portion of the brain is cooled by not more than 4.degree. C.,
wherein the cooling device comprises a passive cooling device
having a highly thermally conductive portion adjacent the exposed
portion of dura mater. See, for example, U.S. patent application
Ser. No. 13/482,903 published as U.S. 2012/0290052 and U.S. Pat.
No. 8,591,562, each of which is hereby incorporated by reference in
their entirety.
[0014] In certain instances, it may be beneficial to have the skull
of the patient intact covering, for example, the epileptic focus or
portion of the brain under which the passive cooling device
resides. For example, a patient may be in an area where the ambient
temperature is above the patient's body temperature. In such an
instance, the transcranial device would direct heat from the
surrounding environment to the brain, which is believed to be the
opposite of the preferred direction.
[0015] Accordingly, in one aspect the present disclosure provides a
thermally conductive graft comprising: a thermally conductive
matrix, wherein the thermally conductive graft comprises a first
surface, a second surface, and a thermally conductive matrix
disposed between the first and second surfaces.
[0016] In a second aspect the present disclosure provides a method
of passively cooling a hyperthermic region of the central nervous
system comprising: implanting a thermally conductive graft adjacent
to the hyperthermic region of the central nervous system, wherein
the thermally conductive graft is effective to conduct heat from
the hyperthermic region to another region.
[0017] In a third aspect the present disclosure provides a method
of preventing or treating a neurological abnormality comprising:
implanting a thermally conductive graft adjacent to a hyperthermic
region of the central nervous system, wherein the thermally
conductive graft conducts heat from the hyperthermic region to a
region of the central nervous system that is not hyperthermic.
[0018] In a fourth aspect the present disclosure provides a method
of preventing or treating inflammation of the central nervous
system comprising: implanting a thermally conductive graft adjacent
to a hyperthermic region of the central nervous system, wherein the
thermally conductive graft conducts heat from the hyperthermic
region to a region of the central nervous system that is not
hyperthermic.
[0019] In a fifth aspect the present disclosure provides a method
of preventing or treating a neurological abnormality comprising
implanting a thermally conductive graft adjacent to a hyperthermic
region of a central nervous system of a subject. In various
examples, the thermally conductive graft comprises a first surface,
a second surface, and a thermally conductive matrix disposed
between the first and second surfaces
BRIEF DESCRIPTION OF THE DRAWINGS
[0020] The foregoing aspects and many of the attendant advantages
of this invention will become more readily appreciated as the same
become better understood by reference to the following detailed
description, when taken in conjunction with the accompanying
drawings, wherein:
[0021] FIG. 1 depicts representations of infrared thermal images of
rats with fluid-percussion injury.
[0022] FIG. 2A depicts a representation of an infrared image at the
time of cortical resection for right frontal intractable
epilepsy.
[0023] FIG. 2B depicts independent determination of the seizure
focus from the view point shown in FIG. 2A.
[0024] FIG. 2C depicts pre-resection from the view point shown in
FIG. 2A.
[0025] FIG. 3 illustrates relative expression of genes encoding
pro-inflammatory cytokines after head injury in the rat.
[0026] FIG. 4A depicts a central nervous system graft according to
an example embodiment of the present disclosure.
[0027] FIG. 4B depicts a central nervous system graft wherein the
central nervous system graft is extended through an opening in the
skull to a subgaleal space, in accordance with an example
embodiment of the present disclosure.
[0028] FIG. 4C depicts a central nervous system graft replacing a
portion of removed dura, in accordance with an example embodiment
of the present disclosure.
[0029] FIG. 4D depicts the central nervous system graft of FIG. 4C,
and further includes an illustration of passive heat dissipation
from hyperthermic regions of the brain, in accordance with an
example embodiment of the present disclosure.
DETAILED DESCRIPTION
[0030] FIG. 1 depicts representations of infrared thermal imaging
of rats with fluid-percussion injury. In the top panels 102 and
104, representations of thermal images of `no seizure` rat brains
are depicted. In top panels 102 and 104, only large veins in the
posterior aspect of the cranial window at sites 106 and 108 show
increased temperature (0.38.+-.0.1.degree. C. from hottest spot to
rest of the cortex). In the bottom panels 112 and 114, two animals
with many seizures show increased temperature (1.0.+-.0.1.degree.
C.) along the edge of the neocortical injury at sites 116 and 118,
relative to surrounding cooler areas of the cortex. The graph 110
depicts the relationship between seizure frequency and temperature
intensity.
[0031] The presence of neocortical, hyperthermic "hot spots" in
head-injured rats (shown in FIG. 1) and in drug resistant epilepsy
patients (shown in FIGS. 2A-2C) may be observed using infrared
thermal imaging. The hyperthermic "hot spots" may coincide with the
positions of epileptic foci identified by electrocorticography
("ECoG") in head-injured rats. FIG. 2A depicts a representation of
an infrared image of a human epilepsy patient at the time of
cortical resection for right frontal intractable epilepsy. The
representation of the thermal image in FIG. 2A shows a higher
temperature `hot spot` 202 in the frontal region (i.e., the left
side of the exposure) relative to the surrounding cortex. For
example, the patient depicted in FIG. 2A experienced a peak
temperature of 39.3.degree. C. at hot spot 202 in the frontal
region, while the entire exposed cortex including the hot spot 202
experienced a temperature of 37.1.degree. C. FIG. 2B depicts
independent determination of the seizure focus, with the superior
frontal region being the ictal onset zone with resection of this
area evident in the post-operative photograph. FIG. 2C depicts
pre-resection from the same viewpoint as FIG. 2A.
[0032] In both head injured epileptic rats and humans, hot spots
are evident during anesthesia, which fully controls epileptic
activity (Eastman et al., 2010). Thus, the hot spots are not
directly attributable to seizures or seizure-induced changes in
regional cerebral blood flow, but to a more chronic process such as
inflammation.
[0033] Regions of increased temperature that overlap with ictal
onset zones (e.g., hot spot 202 of FIG. 2A) have been observed in
human epilepsy patients who were studied, under anesthesia, during
implantation of grids used for diagnosis and localization of their
epileptic foci. The ictal onset zones were warmer than surrounding
tissue by 2.degree. C. or more.
[0034] These observations demonstrate that epileptic foci in both
animals and humans are hyperthermic, i.e. at a higher temperature
than the normal brain.
[0035] Mild-passive cooling with trans-cranial devices can be used
to treat epilepsy. See, e.g., U.S. patent application Ser. No.
13/482,903 and U.S. Pat. No. 8,591,562, each of which is
incorporated herein by reference in its entirety.
[0036] FIG. 3 illustrates relative expression of genes encoding
pro-inflammatory cytokines after head injury in the rat. Mild
passive focal cooling in the rat brain may be associated with
anti-inflammatory effects. In the example depicted in FIG. 3,
expression was measured in the contra- and ipsilateral neocortices
of head injured rats randomized to cooling or no treatment, and in
naive controls (n=7 animals per group), 1 week after injury (after
4 days of cooling). Expression was normalized to the geometric mean
of 3 housekeeping genes with statistical comparison at p<0.05
vs. control.
[0037] Epileptic foci are inflamed and mild focal cooling is
anti-inflammatory. In FIG. 3, anti-inflammatory effect on the
inflamed epileptic focus is realized using mild focal cooling by
2.degree. C. RT-PCR was used to examine the gene expression of pro-
and anti-inflammatory cytokines after injury (4 days after cooling)
before the appearance of focal seizures. Pro-inflammatory cytokines
known to be involved in post-traumatic sequelae and epileptogenesis
were elevated by FPI, and decreased by mild cooling. In particular,
mild cooling had a dramatic effect on IL-1.beta. nd caspase-1, both
implicated in epileptogenesis. TGF-2(3 expression, which has not
been implicated in epileptogenesis or TBI, was not affected by head
injury or by cooling.
[0038] FIG. 4A depicts a system 400 including a thermally
conductive graft 420 according to an example embodiment of the
present disclosure. Thermally conductive graft 420 may be sized and
configured to overlay the dura 402. Dura 402 may be a thick
membrane that is the outermost of the three layers of the meninges
that surround the brain 408 and spinal cord. In various examples,
thermally conductive graft 420 may be sized, shaped and configured
to fit in epidural space 410 between dura 402 and the skull of the
patient.
[0039] A portion of skull 406 may be removed in a craniotomy to
allow for placement of thermally conductive graft 420 between the
skull and dura 402 in epidural space 410. In various examples, once
thermally conductive graft 420 is placed overlaying dura 402,
replacement of portion of skull 406 may compress thermally
conductive graft 420. Such compression may effectively hold
thermally conductive graft 420 in the desired position relative to
the hyperthermic focus 414. As shown in FIG. 4A, thermally
conductive graft 420 may be positioned so as to extend laterally
beyond the edges of the craniotomy such that thermally conductive
graft 420 underlies the entirety of portion of skull 406, and
extends beyond the edges of the incision in the skull made during
the craniotomy. In some other examples, thermally conductive graft
420 may underlie less than the entirety of portion of skull 406
removed during the craniotomy.
[0040] For the thermally conductive grafts depicted in FIGS. 4A-D,
where the patient has a single epileptic and/or hyperthermic focus
414 in the patient's brain, thermally conductive graft 420 may be
sized, positioned, and/or configured to overlay all, or
substantially all of epileptic and/or hyperthermic focus 414. In
some examples, thermally conductive graft 420, as depicted in FIGS.
4A-D, may be sized, positioned, and/or configured to overlay a
portion of epileptic and/or hyperthermic focus 414. For example,
thermally conductive graft 420 may be positioned to overlay
.about.10-90% of epileptic and/or hyperthermic focus 414. In some
other examples where the patient has multiple epileptic and/or
hyperthermic foci 414, thermally conductive graft 420 may be sized,
positioned, and/or configured to overlay all of the epileptic
and/or hyperthermic foci 414 or a subset of all of the epileptic
and/or hyperthermic foci 414.
[0041] In various examples, thermally conductive graft 420 may
include a thermally conductive matrix. In some examples, the
thermally conductive matrix may include a biocompatible matrix and
a thermally conductive material embedded into the biocompatible
matrix. A biocompatible material may be, for example, a material
that is suitable for contact with bodily tissues and fluids because
it does not cause an allergic reaction, immune response, or other
significant adverse side effects. A matrix may be, for example, a
three dimensional structure or scaffolding which may comprise
repetitive polymeric elements at a molecular level. In various
examples, the biocompatible matrix may include silicon, collagen,
carbohydrate chains, expanded polytetrafluoroethylene,
polylactides, polyglycolides, gelatin, agar, cellulose-based
compounds, thermally conductive polymers, pericranium harvested
from the patient, fascia lata, tissue harvested via autograph,
allograph, and/or xenograph, and combinations thereof. In various
examples, the thermally conductive material may include thermally
conductive polymers, graphene, carbon nanotubes, diamond, metal
powders, metal beads, and combinations thereof.
[0042] In various examples, thermally conductive graft 420 may be
formed in such a way as to include one or more apertures extending
from one substantially planar surface of thermally conductive graft
420 to another substantially planar surface of thermally conductive
graft 420. Such an aperture (not shown) may allow fluid to drain
between the substantially planar surfaces of thermally conductive
graft 420 (e.g., from epidural space 410 to subgaleal space 412).
In various other examples, thermally conductive graft 420 may
include an aperture configured to allow fluid to drain laterally
from one portion of thermally conductive graft 420 to the other.
For example, thermally conductive graft 420 may be formed in such a
way as to include an aperture (not shown) which extends in a
direction that is parallel to the substantially planar opposed
surfaces of thermally conductive graft 420. Such an aperture may
allow fluid to drain laterally, from one portion of the thermally
conductive graft to another (e.g., from the left hemisphere of the
brain to the right hemisphere).
[0043] In some examples, the thermally conductive material may be
dispersed throughout the biocompatible matrix of thermally
conductive graft 420 in a uniform or semi-uniform manner. In an
example, graphene may be the thermally conductive material. In the
example, graphene powder may be diluted in a mixture of alcohol and
water to form a solution. The water may be allowed to evaporate.
Silicone may be mixed with the solution. The graphene may be evenly
distributed into the silicone through mixing or homogenization
prior to the silicone curing. The silicon may then cure and the
alcohol may evaporate. In the example, silicon may comprise the
biocompatible matrix with graphene comprising a thermally
conductive material dispersed throughout the biocompatible matrix.
In some examples, thermally conductive graft 420 may comprise a
liquid or aerosol which forms into a solid or semi-solid
biocompatible matrix, through, for example, exposure to an
activator agent or exposure to the atmosphere.
[0044] In various other examples, thermally conductive graft 420
may comprise a thermally conductive metal sheet including
biocompatible material such as titanium. In examples where
thermally conductive graft 420 comprises a metal sheet, the
thermally conductive graft 420 may be made to conform to the
contours of the skull, dura, and/or brain of the particular patient
into whom the thermally conductive graft 420 is to be implanted.
For example, a thermally conductive titanium sheet may be 3D
printed based on the curvature of a portion of the patient's skull
which may have one or more underlying hyperthermic foci. In various
examples, a thermally conductive metal sheet may be formed with a
thickness of between 1 and 4 millimeters. In examples where
thermally conductive graft 420 comprises a metal sheet, portion of
skull 406 may be filed, shaved, or otherwise reduced according to
the thickness of the metal sheet to allow space for thermally
conductive graft 420 between the skull and the meningeal layer.
[0045] Thermally conductive graft 420 may be effective to conduct
heat from a hyperthermic region to another region as shown by
arrows in FIG. 4A. For example, thermally conductive graft 420 may
be effective to conduct heat from a hyperthermic region on or in
the patient's brain to a surrounding, cooler area of the patient's
cortex. Thermally conductive graft 420 may at least partially
overlay hyperthermic focus 414, which may be, for example, an
epileptic focus, inflammation site, or other area of the brain with
an elevated temperature relative to surrounding tissue. For
example, hyperthermic focus 414 may have a temperature that is
higher than 37.degree. C. In another example, hyperthermic focus
414 may have a temperature that is higher than an average
temperature of brain 408. Thermally conductive graft 420 may be
comprised of a suitable material effective to passively conduct
heat from the hotter epileptic focus or inflammation site to cooler
surrounding areas of the patient's cortex.
[0046] In various examples, thermally conductive graft 420 may
include substantially planar opposed surfaces. For example, a first
substantially planar surface of thermally conductive graft 420 may
be disposed adjacent to the skull of the patient while a second
substantially planar surface of thermally conductive graft 420 may
be disposed adjacent to a meningeal membrane of the patient, such
as, for example, dura 402. In another example, a substantially
planar surface of thermally conductive graft 420 may be disposed
adjacent to the patient's brain. Although surfaces of thermally
conductive graft 420 are described in various examples herein as
including substantially planar opposed surfaces, such surfaces may
curve to conform to the contours of the patient's skull, meningeal
membrane, and/or brain, as appropriate.
[0047] In various examples, one or more of the substantially planar
opposed surfaces may include a coating. For example, a planar
surface of thermally conductive graft 420 may be coated with an
adhesive material or may be formed in such a way as to adhere to
the meninges of a patient. In some examples, a planar opposed
surface of thermally conductive graft 420 may include grips, teeth,
protrusions, and/or a sticky or tactile surface effective to
prevent the thermally conductive graft 420 from sliding or becoming
dislodged after being positioned by a surgeon. In some other
examples, one or more of the substantially planar opposed surfaces
of thermally conductive graft 420 may include a coating or surface
that is non-scarring to the meninges of the patient. In various
other examples, a surface of thermally conductive graft 420 may
include a medicament or non-fouling coating. Non-fouling coatings
may include, for example, polyethylene glycol (PEG) and/or
zwitterionic polymers. In various examples, the medicament or
non-fouling coating may aid in the prevention of infection and/or
may have an anti-inflammatory effect.
[0048] FIG. 4B depicts thermally conductive graft 420, wherein the
thermally conductive graft 420 is extended through an opening in
the skull to a subgaleal space 412, in accordance with an example
embodiment of the present disclosure. Subgaleal space 412 may be,
for example, an area between the skull and the scalp. As depicted
in FIG. 4B, thermally conductive graft 420 may be disposed between
dura 402 and the skull and may be disposed in a channel 422 which
extends through the skull from epidural space 410 to subgaleal
space 412. Channel 422 may be, for example, a burr hole, aperture,
or other incision in the skull. For example, channel 422 may be an
incision formed during a craniotomy. As depicted in FIG. 4B,
thermally conductive graft 420 may extend from epidural space 410
through channel 422 and laterally in one or more directions from
channel 422 in subgaleal space 412. Such a configuration may allow
heat to dissipate from hyperthermic focus 414 to cooler regions of
the brain and also to the scalp through channel 422.
[0049] In some examples, channel 422 and thermally conductive graft
420 may be used in conjunction with an active heat pump to transfer
heat to or from the brain. For example, a Peltier device or other
heat pump may be coupled to the patient's scalp, the portion of
thermally conductive graft 420 in subgaleal space 412, or directly
to the portion of the thermally conductive graft 420 residing in
channel 422. The Peltier device or other heat pump may be activated
to accelerate the flow of heat from hyperthermic focus 414 through
thermally conductive graft 420 (including the portion of thermally
conductive graft 420 residing in channel 422) to the environment
outside the patient's head.
[0050] FIG. 4C depicts thermally conductive graft 420 replacing a
portion of removed dura 402, in accordance with an example
embodiment of the present disclosure. In such embodiments, the
surgeon may remove a portion of native dura 402 and/or other
meningeal layers and replace the removed portion with thermally
conductive graft 420 rather than overlaying thermally conductive
graft 420 on top of dura 402. For example, the patient's native
dura may become damaged as a result of head trauma. The damaged
native dura may be replaced with thermally conductive graft 420. In
examples where thermally conductive graft 420 replaces native dura
402, thermally conductive graft may be of approximately the same
thickness, or slightly thicker than, native dura 402. Heat
dissipation properties of thermally conductive graft 420 may have
beneficial anti-inflammatory effects at the site of the traumatic
brain injury.
[0051] In some examples, thermally conductive graft 420 may
comprise a suturable material, such as a suturable collagen, and
may be sutured to the surrounding dura 402 and/or to the other
surrounding meningeal layers. In various examples, suturing
thermally conductive graft 420 may prevent leakage of spinal fluid.
In some other examples, thermally conductive graft 420 may be a
non-suturable biocompatible matrix and may be compressed into a
"well" or "divot" left by the removal of a portion of dura 402
and/or other meningeal layers. Compression of non-suturable
thermally conductive graft 420 may be caused by replacement of
portion of skull 406 which was removed during a craniotomy.
Compression of thermally conductive graft 420 may prevent leakage
of spinal fluid between the remaining native dura 402 and thermally
conductive graft 420. In some examples, replacing a portion of dura
402 with thermally conductive graft 420 may allow for efficient
dissipation of heat from hyperthermic focus 414 to cooler portions
of the brain. For example, heat may be conducted through thermally
conductive graft 420 to cooler portions of the brain relative to
hyperthermic focus 414, as shown by arrows in FIG. 4C.
Additionally, the removed portion of dura 402 is no longer able to
act as a heat-insulating layer on top of the brain which may
further increase the efficiency of heat transfer away from
hyperthermic focus 414.
[0052] In various embodiments, one or more heat pipes may be
thermally coupled to thermally conductive graft 420. For example, a
heat pipe may be positioned within the brain of the patient and may
be effective to transfer heat away from a hyperthermic focus 414
which lies below the surface of the brain. A first end of a heat
pipe may extend into the brain to an area which is proximate to the
hyperthermic focus. A second end of the heat pipe may be embedded
in, or otherwise coupled to, thermally conductive graft 420. In
such an example, heat may be transferred from the first end of the
heat pipe to the second end of the heat pipe and into the thermally
conductive matrix. Heat may then be transferred through the
thermally conductive matrix to cooler portions of the brain and/or
to the scalp, according to various implementations of thermally
conductive graft 420 described herein.
[0053] FIG. 4D depicts the thermally conductive graft 420 of FIG.
4C, and further includes an illustration of passive heat
dissipation from hyperthermic regions of the brain, in accordance
with an example embodiment of the present disclosure. As shown in
FIG. 4D, replacing a portion of dura 402 with thermally conductive
graft 420 may allow heat to dissipate from a hyperthermic focus to
cooler areas of the brain, lowering the temperature of the focus
until it is no longer hyperthermic. In an example depicted in FIG.
4D, the cured focal hyperthermia region 430 is shown to have a
temperature of 37.degree. C. which is the same as the temperature
at a distal region 432 of brain 408. When a focus is no longer
hyperthermic, the temperature gradient breaks down and the
thermally conductive matrix of thermally conductive graft 420
ceases to transfer heat. Advantageously, if another hyperthermic
focus arises underlying thermally conductive graft 420 at a later
time, thermally conductive graft 420 will resume passive heat
transfer to cooler areas of the brain without requiring any
external input or activation.
[0054] Among other potential benefits, a thermally conductive graft
420 arranged in accordance with various embodiments described
herein may be used to treat or prevent seizures. Additionally, in
some embodiments, a thermally conductive graft 420 may be used to
reduce inflammation by cooling inflamed areas, such as a site of
traumatic injury. Reduction of inflammation may in turn reduce
scarring which may be beneficial particularly in the context of
follow-up procedures where native and/or non-native materials may
fuse together via scar tissue. Additionally, although described
herein primarily in the context of brain surgery, thermally
conductive grafts may also be used in different contexts to focally
cool hyperthermic areas of tissue. For example, thermally
conductive grafts as described herein may be used to focally cool
an inflamed area following removal of a spinal cord tumor or
following other surgery. Furthermore, the thermally conductive
graft may continue to automatically function to transfer heat in
case of a reoccurrence of a hyperthermic region or a newly arisen
hyperthermic focus.
[0055] In accordance with the above discovery, in one aspect, the
present disclosure provides a thermally conductive graft 420
comprising a thermally conductive matrix, wherein the central
nervous system graft has substantially planar opposed surfaces and
is sized and configured to fit between the brain and the skull.
[0056] As used herein, the "central nervous system" is the part of
the nervous system that integrates information it receives from,
and coordinates and influences the activity of, all parts of the
body of a bilaterally symmetric animal. It includes the brain,
spinal cord, and proximal ganglia.
[0057] In certain embodiments, thermally conductive graft 420 is
sized and configured to replace a meningeal membrane. In certain
other embodiments, thermally conductive graft 420 is sized and
configured to overlay a native meningeal membrane.
[0058] In certain embodiments, thermally conductive graft 420
further comprises at least one thermally conductive subcutaneous
strip that extends away from the graft surface and is configured to
be positioned adjacent to the meninges. In certain further
embodiments, the thermally conductive graft 420 is sized and
configured to extend beyond the edge of a craniotomy through to a
subgaleal space.
[0059] In a second aspect, the present disclosure provides a method
of passively cooling a hyperthermic region of the central nervous
system comprising implanting a thermally conductive graft adjacent
to a hyperthermic region of the central nervous system, wherein the
thermally conductive graft conducts heat from the hyperthermic
region to another region.
[0060] As used herein, a "hyperthermic region" of a brain is an
area of the brain that has an abnormally high temperature. In
certain embodiments, the hyperthermic region has temperature above
37.degree. C. prior to treatment. In certain embodiments, the
hyperthermic region of the brain has a temperature that is higher
than the average temperature of the brain.
[0061] In certain embodiments of the present disclosure, the
hyperthermic region is an epileptic focus.
[0062] As used herein, an "epileptic focus" is the location of the
epileptic abnormality or area from which seizures may develop.
[0063] In certain embodiments, the method further comprises
removing a portion of the dura mater adjacent to the hyperthermic
region.
[0064] In certain embodiments, the method further comprises
replacing the portion of the cranium adjacent to the hyperthermic
region.
[0065] In certain embodiments, the thermally conductive central
nervous system graft is sized and shaped to substantially overlay
the hyperthermic region and extend away from the hyperthermic
region between the brain and the skull.
[0066] In a third aspect, the present disclosure provides a method
of preventing or treating a neurological abnormality comprising:
implanting a thermally conductive graft adjacent to a hyperthermic
region of the central nervous system, wherein the thermally
conductive graft conducts heat from the hyperthermic region to a
region of the central nervous system that is not hyperthermic.
[0067] In certain embodiments, the neurological abnormality is
selected from a group consisting of epilepsy, stroke, and traumatic
brain injury.
[0068] In certain embodiments, the neurological abnormality is
epilepsy. In various embodiments, the pathological effect or
symptom of epilepsy may comprise at least one of convulsive
seizures, focal seizures, and generalized seizures (including
tonic-clonic, tonic, clonic, myoclonic, absence, and atonic
seizures), and a post-ictal state of confusion.
[0069] In certain embodiments, the method further comprises
removing a portion of the dura mater adjacent to the hyperthermic
region.
[0070] In certain embodiments, the method further comprises
replacing the portion of the cranium adjacent to the hyperthermic
region.
[0071] In certain embodiments, the thermally conductive central
nervous system graft is sized and shaped to substantially overlay
the hyperthermic region and extend away from the hyperthermic
region between the brain and the skull.
[0072] In certain other embodiments, the central nervous system
graft is sized and configured to partially cover the hyperthermic
region.
[0073] In certain other embodiments, the central nervous system
graft is sized and configured to be adjacent to the hyperthermic
region. In certain further embodiments, the central nervous system
graft is within 0.1 mm, 0.2 mm, 0.3 mm, 0.4 mm. 0.5 mm, 0.6 mm, 0.7
mm, 0.8 mm, 0.9 mm, 1.0 mm, or more away from the hyperthermic
region.
[0074] In a fourth aspect the present application provides a method
of preventing or treating inflammation of the central nervous
system comprising: implanting a thermally conductive graft adjacent
to a hyperthermic region of the central nervous system, wherein the
thermally conductive graft conducts heat from the hyperthermic
region to a region of the central nervous system that is not
hyperthermic.
[0075] Definitions and explanations used in the present disclosure
are meant and intended to be controlling in any future construction
unless clearly and unambiguously modified in the following examples
or when application of the meaning renders any construction
meaningless or essentially meaningless. In cases where the
construction of the term would render it meaningless or essentially
meaningless, the definition should be taken from Webster's
Dictionary, 3rd Edition or a dictionary known to those of ordinary
skill in the art, such as the Oxford Dictionary of Biochemistry and
Molecular Biology (Ed. Anthony Smith, Oxford University Press,
Oxford, 2004).
[0076] Advantages of the devices and methods according to the
present application.
[0077] First, a thermally conductive graft may require simple
materials to build. The portion of the skull removed during surgery
can be merely replaced. The technology to create gel or silicone
pads already exists. Similarly, collagen based autograph,
allograph, and zenograph dural replacements exist in various forms
and can be augmented in accordance with the present technology.
[0078] Second, the cooling action is not significantly affected by
the temperature of the scalp. This might be an issue when the
epilepsy patient remains in a particularly cold environment for a
protracted period of time. The scalp could cool below body
temperature, thus further cooling the underlying portion of the
brain.
[0079] Third, the amount of treatment is directly related to the
pathology to be addressed (e.g. focal hyperthermia). For example,
the warmer the inflamed region of the central nervous system, the
greater the cooling effect. If the central nervous system tissue
dis-inflames over time and the temperature normalizes, the
temperature gradient collapses, and the thermally conductive graft
will automatically terminate the cooling effect. The thermally
conductive graft may also resume passive cooling in case of
recrudescence of the pathological hyperthermia.
[0080] Fourth, the thermally conductive graft can be conveniently
used in a variety of neurosurgical applications, where acute
inflammation complicates outcome. By replacing a portion of the
dura and cooling the underlying brain tissue, the thermally
conductive graft may produce an anti-inflammatory treatment that
may prove beneficial for a wide range of brain injuries or
neurological disorders, and also to abate acute inflammation after
any neurosurgical treatment of a portion of the central nervous
system. Such passive cooling may improve the outcome of almost any
neurosurgical treatment.
[0081] As will be understood by one of ordinary skill in the art,
each embodiment disclosed herein can comprise, consist essentially
of or consist of its particular stated element, step, ingredient or
component. As used herein, the transition term "comprise" or
"comprises" means includes, but is not limited to, and allows for
the inclusion of unspecified elements, steps, ingredients, or
components, even in major amounts. The transitional phrase
"consisting of" excludes any element, step, ingredient or component
not specified. The transition phrase "consisting essentially of"
limits the scope of the embodiment to the specified elements,
steps, ingredients or components and to those that do not
materially affect the embodiment.
[0082] Unless otherwise indicated, all numbers expressing
quantities of ingredients, properties such as molecular weight,
reaction conditions, and so forth used in the specification and
claims are to be understood as being modified in all instances by
the term "about." Accordingly, unless indicated to the contrary,
the numerical parameters set forth in the specification and
attached claims are approximations that may vary depending upon the
desired properties sought to be obtained by the present invention.
At the very least, and not as an attempt to limit the application
of the doctrine of equivalents to the scope of the claims, each
numerical parameter should at least be construed in light of the
number of reported significant digits and by applying ordinary
rounding techniques. When further clarity is required, the term
"about" has the meaning reasonably ascribed to it by a person
skilled in the art when used in conjunction with a stated numerical
value or range, i.e. denoting somewhat more or somewhat less than
the stated value or range, to within a range of .+-.20% of the
stated value; .+-.19% of the stated value; .+-.18% of the stated
value; .+-.17% of the stated value; .+-.16% of the stated value;
.+-.15% of the stated value; .+-.14% of the stated value; .+-.13%
of the stated value; .+-.12% of the stated value; .+-.11% of the
stated value; .+-.10% of the stated value; .+-.9% of the stated
value; .+-.8% of the stated value; .+-.7% of the stated value;
.+-.6% of the stated value; .+-.5% of the stated value; .+-.4% of
the stated value; .+-.3% of the stated value; .+-.2% of the stated
value; or .+-.1% of the stated value.
[0083] Notwithstanding that the numerical ranges and parameters
setting forth the broad scope of the invention are approximations,
the numerical values set forth in the specific examples are
reported as precisely as possible. Any numerical value, however,
inherently contains certain errors necessarily resulting from the
standard deviation found in their respective testing
measurements.
[0084] Groupings of alternative elements or embodiments of the
invention disclosed herein are not to be construed as limitations.
Each group member may be referred to and claimed individually or in
any combination with other members of the group or other elements
found herein. It is anticipated that one or more members of a group
may be included in, or deleted from, a group for reasons of
convenience and/or patentability. When any such inclusion or
deletion occurs, the specification is deemed to contain the group
as modified thus fulfilling the written description of all Markush
groups used in the appended claims.
[0085] Certain embodiments of this invention are described herein,
including the best mode known to the inventors for carrying out the
invention. Of course, variations on these described embodiments
will become apparent to those of ordinary skill in the art upon
reading the foregoing description. The inventor expects skilled
artisans to employ such variations as appropriate, and the
inventors intend for the invention to be practiced otherwise than
specifically described herein. Accordingly, this invention includes
all modifications and equivalents of the subject matter recited in
the claims appended hereto as permitted by applicable law.
Moreover, any combination of the above-described elements in all
possible variations thereof is encompassed by the invention unless
otherwise indicated herein or otherwise clearly contradicted by
context.
[0086] Furthermore, numerous references have been made to patents
and printed publications throughout this specification. Each of the
above-cited references and printed publications are individually
incorporated herein by reference in their entirety.
[0087] In closing, it is to be understood that the embodiments of
the invention disclosed herein are illustrative of the principles
of the present invention. Other modifications that may be employed
are within the scope of the invention. Thus, by way of example, but
not of limitation, alternative configurations of the present
invention may be utilized in accordance with the teachings herein.
Accordingly, the present invention is not limited to that precisely
as shown and described.
[0088] The particulars shown herein are by way of example and for
purposes of illustrative discussion of the preferred embodiments of
the present invention only and are presented in the cause of
providing what is believed to be the most useful and readily
understood description of the principles and conceptual aspects of
various embodiments of the invention. In this regard, no attempt is
made to show structural details of the invention in more detail
than is necessary for the fundamental understanding of the
invention, the description taken with the drawings and/or examples
making apparent to those skilled in the art how the several forms
of the invention may be embodied in practice.
* * * * *